Savannas constitute the most fire-prone biome on Earth and annual emissions from savanna-burning activities are a globally important source of greenhouse-gas (GHG) emissions. Here, we describe the ...application of a commercial fire-management program being implemented over 28 000 km
2
of savanna on Aboriginal lands in northern Australia. The project combines the reinstatement of Aboriginal traditional approaches to savanna fire management - in particular a strategic, early dry-season burning program - with a recently developed emissions accounting methodology for savanna burning. Over the first 7 years of implementation, the project has reduced emissions of accountable GHGs (methane, nitrous oxide) by 37.7%, relative to the pre-project 10-year emissions baseline. In addition, the project is delivering social, biodiversity, and long-term biomass sequestration benefits. This methodological approach may have considerable potential for application in other fire-prone savanna settings.
Background Evaluation of cardiovascular safety for new therapies for COPD is important because of a high prevalence of cardiac comorbidities in the COPD population. Hence, we evaluated the effects of ...roflumilast, a novel oral phosphodiesterase 4 inhibitor developed for the treatment and prevention of COPD exacerbations, on major adverse cardiovascular events (MACEs). Methods Intermediate- and long-term placebo-controlled clinical trials of roflumilast in COPD were pooled and assessed for potential cardiovascular events. Studies comprised 14 12- to 52-week placebo-controlled trials in patients with moderate to very severe COPD. All deaths and serious nonfatal cardiovascular events were evaluated by an independent adjudication committee blinded to study and treatment. The MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke was analyzed according to treatment group. Results Of 6,563 patients receiving roflumilast, 52 experienced MACEs (14.3 per 1,000 patient-years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient-years). The MACE composite rate was significantly lower for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019). Conclusions A lower rate of cardiovascular events was observed with roflumilast than with placebo in patients with COPD, indicating the lack of a cardiovascular safety signal when treating patients with COPD. Potential cardiovascular benefits of roflumilast should be evaluated in future controlled clinical trials.
The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in ...an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.
•Sodium silicate was less effective in reducing lead release than pH adjustment.•Sodium silicate could promote formation of lead-rich colloidal dispersions.•Scale analysis showed signs of ...incorporation of silica in the pipe scale.•Orthophosphate in combination with pH adjustment was the most effective treatment.
Sodium silicate is thought to mitigate lead release via two mechanisms: by increasing pH and by forming a protective silica film. A pilot-scale study using an excavated lead service line (LSL) fed with water from a Great Lakes source was undertaken to: (1) clearly distinguish the pH effect and the silica effect; (2) compare sodium silicate to orthophosphate and pH adjustment; (3) determine the nature of silica accumulation in the pipe scale. The LSL was cut into segments and acclimated with water at pH 7.1. Median dissolved lead was 197 µg/L in the last 8 weeks of acclimation and dropped to 16 µg/L, 54 µg/L, and 85 µg/L following treatment with orthophosphate (dose: 2.6 mg-PO4/L, pH: 7.9), pH adjustment (pH: 7.9) and sodium silicate (dose: 20 mg-SiO2/L, pH: 7.9), respectively. When silica dose was increased from 20 mg-SiO2/L to 25 mg-SiO2/L (pH: 8.1), lead release destabilized and increased (median dissolved lead: 141 µg/L) due to formation of colloidal dispersions composed mainly of lead- and aluminum-rich phases as detected by field flow fractionation used with inductively coupled plasma mass spectrometry. Si was present in the scale at a maximum of 2.2 atomic % after 17 weeks of silica dosing at 20 mg- SiO2/L. Under the conditions tested, sodium silicate did not offer any benefits for reducing lead release from this LSL other than increasing pH. However, sodium silicate resulted in lower levels of biofilm accumulation on pipe walls, as measured by heterotrophic plate counts, when compared to orthophosphate.
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Abstract Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned ...nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.
For the Western North America Mercury Synthesis, we compiled mercury records from 165 dated sediment cores from 138 natural lakes across western North America. Lake sediments are accepted as faithful ...recorders of historical mercury accumulation rates, and regional and sub-regional temporal and spatial trends were analyzed with descriptive and inferential statistics. Mercury accumulation rates in sediments have increased, on average, four times (4×) from 1850 to 2000 and continue to increase by approximately 0.2μg/m2 per year. Lakes with the greatest increases were influenced by the Flin Flon smelter, followed by lakes directly affected by mining and wastewater discharges. Of lakes not directly affected by point sources, there is a clear separation in mercury accumulation rates between lakes with no/little watershed development and lakes with extensive watershed development for agricultural and/or residential purposes. Lakes in the latter group exhibited a sharp increase in mercury accumulation rates with human settlement, stabilizing after 1950 at five times (5×) 1850 rates. Mercury accumulation rates in lakes with no/little watershed development were controlled primarily by relative watershed size prior to 1850, and since have exhibited modest increases (in absolute terms and compared to that described above) associated with (regional and global) industrialization. A sub-regional analysis highlighted that in the ecoregion Northwestern Forest Mountains, <1% of mercury deposited to watersheds is delivered to lakes. Research is warranted to understand whether mountainous watersheds act as permanent sinks for mercury or if export of “legacy” mercury (deposited in years past) will delay recovery when/if emissions reductions are achieved.
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•We compiled Hg records from lakes across western North America.•Hg accumulation rates increased, on average, four times from 1850 to 2000.•Regional and global emissions of Hg to the atmosphere result in enhanced Hg deposition.•Watershed disturbance exacerbates the problem, by reducing the retention of Hg in soils.•Hg deposition rates are highest near urban areas, where watershed disturbance is greatest.
Diacylglycerol (DAG) is a key lipid second messenger downstream of cellular receptors that binds to the C1 domain in many regulatory proteins. Protein kinase C (PKC) isoforms constitute the most ...prominent family of signaling proteins with DAG-responsive C1 domains, but six other families of proteins, including the chimaerins, Ras-guanyl nucleotide–releasing proteins (RasGRPs), and Munc13 isoforms, also play important roles. Their significant involvement in cancer, immunology, and neurobiology has driven intense interest in the C1 domain as a therapeutic target. As with other classes of targets, however, a key issue is the establishment of selectivity. Here, using 3Hphorbol 12,13-dibutyrate (3HPDBu) competition binding assays, we found that a synthetic DAG-lactone, AJH-836, preferentially binds to the novel PKC isoforms PKCδ and PKC∈ relative to classical PKCα and PKCβII. Assessment of intracellular translocation, a hallmark for PKC activation, revealed that AJH-836 treatment stimulated a striking preferential redistribution of PKC∈ to the plasma membrane relative to PKCα. Moreover, unlike with the prototypical phorbol ester phorbol 12-myristate 13-acetate (PMA), prolonged exposure of cells to AJH-836 selectively down-regulated PKCδ and PKC∈ without affecting PKCα expression levels. Biologically, AJH-836 induced major changes in cytoskeletal reorganization in lung cancer cells, as determined by the formation of membrane ruffles, via activation of novel PKCs. We conclude that AJH-836 represents a C1 domain ligand with PKC-activating properties distinct from those of natural DAGs and phorbol esters. Our study supports the feasibility of generating selective C1 domain ligands that promote novel biological response patterns.
Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specific modulators acting ...via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic efforts had recently led to the identification of AJH-836, a DAG-lactone with preferential affinity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9, and MMP10 were among the genes most prominently induced by PMA, an effect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics efforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of differentially regulating PKC isozyme-specific function in cellular models.
Antibodies to blood-stage antigens of
Plasmodium falciparum
play a pivotal role in human immunity to malaria. During parasite development, multiple proteins are trafficked from the intracellular ...parasite to the surface of
P. falciparum
-infected erythrocytes (IEs). However, the relative importance of different proteins as targets of acquired antibodies, and key pathways involved in trafficking major antigens remain to be clearly defined. We quantified antibodies to surface antigens among children, adults, and pregnant women from different malaria-exposed regions. We quantified the importance of antigens as antibody targets using genetically engineered
P. falciparum
with modified surface antigen expression. Genetic deletion of the trafficking protein skeleton-binding protein-1 (SBP1), which is involved in trafficking the surface antigen PfEMP1, led to a dramatic reduction in antibody recognition of IEs and the ability of human antibodies to promote opsonic phagocytosis of IEs, a key mechanism of parasite clearance. The great majority of antibody epitopes on the IE surface were SBP1-dependent. This was demonstrated using parasite isolates with different genetic or phenotypic backgrounds, and among antibodies from children, adults, and pregnant women in different populations. Comparisons of antibody reactivity to parasite isolates with SBP1 deletion or inhibited PfEMP1 expression suggest that PfEMP1 is the dominant target of acquired human antibodies, and that other
P. falciparum
IE surface proteins are minor targets. These results establish SBP1 as part of a critical pathway for the trafficking of major surface antigens targeted by human immunity, and have key implications for vaccine development, and quantifying immunity in populations.
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